Obesity is the main cause of insulin resistance in humans, and, in many individuals, the first step in the development of type 2 diabetes and metabolic syndrome. The adverse metabolic effects of increasing fat mass depend heavily on its anatomical distribution, with visceral white adipose tissue (WAT) driving the development of insulin resistance and associated metabolic diseases (1). In contrast increased subcutaneous WAT is not associated with insulin resistance and, in some circumstances, has even been shown to have protective effects (2, 1).
Expansion of adipose tissue is achieved by increased lipid storage in existing adipocytes and de novo differentiation of preadipocytes. Various autocrine, paracrine and endocrine factors control adipocyte differentiation (3). Among them insulin is important in regulation of differentiation and lipid accumulation in vitro and in vivo (4). White adipose tissue is also an important endocrine organ, secreting various cytokines and hormones (adipokines) regulating whole body metabolism and insulin sensitivity (5, 6, 7).
It was previously identified that a set of developmentally-regulated genes that are differentially expressed in subcutaneous and visceral adipose tissue of mice and men (8). Among these, the patterning gene glypican-4 (Gpc4) is not only differentially expressed in these depots, but its expression in human WAT is also highly correlated with body mass index (BMI) and adipose distribution as measured by waist-to-hip ratio (WHR). Gpc4 belongs to a six member family of glycosylphosphatidylinositol (GPI) anchored heparan sulfate proteoglycans. Lacking transmembrane and intracellular domains, glypicans function as co-receptors for a variety of growth factors including Wnt, BMPs, FGF and Hedgehog (9, 10, 11). Little is known about the signaling functions of Gpc4. Mammalian Gpc4 has been reported to bind to FGF2 via its heparan sulfate chains in neuronal cells and to function as a low affinity receptor for endostatin (12, 13). The role of Gpc4 in adipocytes and its relationship to metabolic regulation remains unknown.